Proper regulation of NF--kB activity is critical to maintain and balance the inflammatory response. Inactivation of the NF--kB complex relies in part on the proteasome-mediated degradation of promoter-bound NF--kB, but the detailed molecular mechanism initiating this process remains elusive. Here, we show that the methylation of the RelA subunit of NF--kB has an important function in this process. Lysine methyltransferase Set9 physically associates with RelA in vitro and in vivo in response to TNF-α stimulation. Mutational and mass spectrometric analyses reveal that RelA is monomethylated by Set9 at lysine residues 314 and 315 in vitro and in vivo. Methylation of RelA inhibits NF--kB action by inducing the proteasome-mediated degradation of promoter-associated RelA. Depletion of Set9 by siRNA or mutation of the RelA methylation sites prolongs DNA binding of NF--kB and enhances TNF-α-induced expression of NF--kB target genes. Together, these findings unveil a novel mechanism by which methylation of RelA dictates the turnover of NF- -kB and controls the NF--kB-mediated inflammatory response.
ASJC Scopus subject areas
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)